S-Adenosyl-L-methionine (AdoMet) is a safe and probably effective antidepressant agent in certain forms of clinical depression. AdoMet is synthesized in every cell by methionine-adenosyltransferase (MAT). In higher mammals there are several tissue specific MAT isozymes differing in kinetic and molecular properties. We postulate that certain forms of clinical depression are due to a deficiency of brain MAT and that the therapeutic effects of AdoMet are related to its ability to correct this biochemical defect.